ICAM-1 is a 90 kDa type I cell surface glycoprotein composed of five extracellular immunoglobulin superfamily domains referred to as domains 1 through 5 and numbered from N to C-terminus, a transmembrane region and an intracellular region (Cell. 1990, 61:243-54). ICAM-1 mediates leukocyte/leukocyte interaction such as interaction between T cells and antigen presenting cells. It also mediates leukocyte extravasation into tissue during inflammatory processes (Transplantation. 1999, 67:729-736). In vitro study showed that antibodies interfering the ICAM-1/leukocyte function antigen-1 (LFA-1) interaction are able to inhibit T cell adhesion to endothelial cells and T cell activation also could be significantly reduced in a mixed lymphocyte reaction by these antibodies (Proc. Natl. Acad. Sci. USA. 1988, 85:3095-3099). In monkey studies using murine monoclonal antibodies against human ICAM-1, R6-5-D6 (enlimomab), renal allograft survival has been prolonged and T cell infiltration in the graft was decreased compared with controls (J. Immunol. 1990, 144:4604-4612). Enlimomab also had been proved to be beneficial in depressing disease activity in patient with rheumatoid arthritis (Arthritis Rheum. 1994, 37:992-999; J. Rheumatol. 1996, 23:1338-1344). However, enlimomab induction therapy after renal transplantation in a randomized multicenter study was not able to reduce the rate of acute rejection or the risk of delayed onset of graft function (Transplantation 1999, 67:729-736). Moreover, clinical trial in acute ischemic stroke patient revealed that anti-ICAM-1 therapy with enlimomab was not an effective and indeed significantly worsen stroke outcome and induced more adverse effect, primarily infections and fever compared with placebo (Neurology 2001, 57:1428-1434). The enlimomab functions by blocking the adhesion of T cells as wells as neutrophils to the vascular endothelial cells and thus it has been suggested that interfering with neutrophil emigration potentially increases the susceptibility to infection (J. Immunol. 1999, 162:2352-2357).
Dendritic cells (DCs) are highly specialized antigen-presenting cells that integrate a variety of immune response (Nature 1998, 382:245-252), and include a heterogeneous family of professional antigen presenting cells involved in initiation of immunity and immunologic tolerance. Until now, immature DCs were believed to induce T-cell anergy, whereas DCs transformed into mature DCs by activation stimuli such as lipopolysaccharide (LPS) were thought to induce primary T cell response (Blood 2006, 108:1435-1440). Furthermore, semimature DCs with a distinctive cytokine production profile might be endowed with tolerogenic functions (Blood 2006, 108:1435-1440).
ICAM-1 is expressed in dendritic cells in high level. Until now, however, ICAM-1 in dendritic cells has been considered to serves as a simple adhesion molecule for LFA-1 binding during T cell-DC interaction.